Pulmonary hypertension
Sitaxsentan Treatment for Patients With Pulmonary Arterial Hypertension Discontinuing Bosentan

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Background

Bosentan, an oral ETA/ETB receptor antagonist, is approved for the treatment of pulmonary arterial hypertension (PAH). However, some patients discontinue bosentan because of hepatotoxicity or inadequate efficacy. Sitaxsentan, an oral, ETA-selective endothelin antagonist currently under investigation, may be an alternative treatment option. In this study we evaluate the safety and efficacy of sitaxsentan in patients discontinuing bosentan.

Methods

Forty-eight patients with idiopathic PAH or PAH associated with connective-tissue disease or congenital heart disease were randomized (double-blind) to a single daily dose of either 50 mg or 100 mg sitaxsentan. Thirty-five of the 48 patients discontinued bosentan because of inadequate efficacy, as judged by the investigator, and 13 discontinued bosentan for safety concerns. Study end-points included change in 6-minute walk distance (6MWD), change in World Health Organization (WHO) functional class, time to clinical worsening, and change in Borg dyspnea score (Borg) from baseline to Week 12.

Results

With 100 mg sitaxsentan, 5 of 15 patients (33%) who discontinued bosentan because inadequate efficacy improved, demonstrating a >15% increase in 6MWD, vs 2 of 20 patients (10%) treated with 50 mg sitaxsentan. Fifteen percent and 20% of these patients had a >15% decrease in 6MWD in the 50- and 100-mg groups, respectively. Similar results were seen for the Borg and WHO functional class. Of the 12 patients discontinuing bosentan because of hepatotoxicity, 1 developed elevated liver enzymes at 13 weeks of sitaxsentan therapy. Overall, sitaxsentan was well tolerated.

Conclusions

Sitaxsentan may represent a safe and efficacious alternative endothelin receptor antagonist for patients discontinuing bosentan.

Section snippets

Patient Selection

Patients between 12 and 75 years of age with PAH, who had discontinued bosentan because of either safety concerns or inadequate efficacy, as determined by the investigator (worsening hemodynamics, lack of clinically significant response, clinically significant worsening in 6MWD and/or worsening in WHO functional class), were eligible if they met the following criteria: (1) PAH that was idiopathic (IPAH), or associated with connective-tissue disease (CTD) or congenital heart defect (CHD), either

Baseline Characteristics

Forty-eight patients were enrolled: 13 (27%) discontinued bosentan because of safety issues and 35 (73%) because of inadequate efficacy. Table 1 shows baseline characteristics of patients by sitaxsentan dose and reason for discontinuing bosentan. Twenty-two patients (46%) had IPAH; 15 (31%) had PAH associated with CTD; and 11 (23%) PAH associated with CHD. The mean baseline 6MWD was 338 meters. Most patients were WHO Class III at baseline (n = 28; 58%). Of note, those patients with WHO Class

Discussion

Over the past several decades, research has prompted new insights into PAH evidence-based treatment; however, the disease remains progressive and fatal in many patients. In 2001, bosentan was the first oral drug approved for treatment of PAH. Bosentan represents a significant clinical advance in the treatment of PAH; however, not all patients tolerate bosentan or adequately improve.16, 33 The question is whether bosentan discontinuation for inadequate efficacy or safety issues implies an

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